Mycophenolic acid glucuronidation

Renal function impairment- Carefully follow patients with severe chronic renal impairment (GFR less than 25 mL/min/1.73 m BSA) for potential adverse reactions due to increase in free mycophenolic acid and total mycophenolic acid glucuronide concentrations. 

Zucker K, Tsaroucha A, Olson L, et al. Evidence that tacrolimus augments the bioavailahility of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 1999 21(l) 35-43. 

Naesens M, Kuypers DR, Streit F, et al. Rifampin induces alterations in mycophenolic acid glucuronidation and elimination implications for drug exposure in renal allograft recipients. Clin Pharmacol Ther 2006 80(5) 509-521. 

Korecka M, Nikolic D, van Breemen RB, Shaw LM. Inhibition of inosine monophosphate dehydrogenase by mycophenolic acid glucuronide is attributable to the presence of trace quantities of mycophenolic acid. Clin Chem 1999 45 1047-50. 

Mycophenolic Mycophenolic acid glucuronide Lacks pharmacological activity but may be associated with dose-limiting (gastrointestinal)... 

The active metabolite of this drug is mycophenolic acid (MPA), which inhibits IMPDH, too. MPA is metabolized in vivo by glucuronidation. It has to be noted that its acyl glucuronide inhibits EVDPDH with similar potency compared to the parent compound. 

Scheme 7.7 Glucuronidation of mycophenolic acid with liver homogenate.

Shipkova, M., Armstrong, V.M., Wieland, E., Niedmann, P.D., Schiitz, E., Brenner-WeiC, G., Voihsel, M., Braun, E. and Oellerich, M., Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Brit. J. Pharmacol., 1999,126, 1075. 

Westley IS, Brogan LR, Morris RG, et al. Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites effect of cyclosporine. Drug Metab Dispos 2006 34(2) 261-266. 

Mojarrabi B, Mackenzie PI. The human UDP glucuronosyltransferase, UGT1A10, glucuronidates mycophenolic acid. Biochem Biophys Res Commun 1997 238 (3) 775-778. 

Mino, Y. et al. Simultaneous determination of mycophenolic acid and its glucuronides in human plasma using isocratic ion-pair high-performance hquid chromatography. J. Pharm. Biomed. 2008,46, 603-608. 

CICLOSPORIN MYCOPHENOLATE 1 plasma concentrations of mycophenolate and of the active metabolite mycophenolic acid Cidosporin is thought to interrupt the enterohepatic circulation of mycophenolate by inhibiting MRP-2 in the biliary tract, which prevents the excretion of its glucuronide Watch for poor response to mycophenolate if cidosporin is added conversely, watch for early features of toxicity if cidosporin is stopped... 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Bowalgaha, K. and Miners, J.O. (2001) The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes. British Journal of Clinical Pharmacology, 52, 605-609. 

Asif, A. R. et al., Proteins identified as targets of the acyl glucuronide metabolite of mycophenolic acid in kidney tissue from mycophenolate mofetil treated rats, Biochimie, 89 (3), 393, 2007. 

Bernard, O., Tojcic, J., Journault, K., Perusse, L., and Guillemette, C. (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab. Dispos. 34 (9), 1539-1545. 

Tacrolimus may inhibit uridine diphosphate glucuronosyltransferase (UGT) which metabolises mycophenolic acid to the glucuronide metabolite, - and may also interfere with the enterohepatic recycling of the glucuronide metabolite. ... 

The addition of mycophenolate mofetil to ciclosporin has been found to reduce the incidence of rejection episodes in kidney transplant patients and it is licensed for combined use. From the studies above, ciclosporin appears to reduce the levels of the active metabolite, mycophenolic acid, and increase the levels of the glucuronide metabolite (which is associated with mycophenolate adverse effects). The UK manufacturers point out that as efficacy studies were conducted in patients using ciclosporin, mycophenolate and corticosteroids, the finding that ciclosporin reduces the mycophenolic acid AUC by 19% to 38% does not affect the recommended dose requirements. They also state that ciclosporin pharmacokinetics are not affected by mycophenolate. However, this is in contrast to the studies... 

T, Suzuki K, Ozono S. Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation. Biol Pharm Bull (2006) 29, 275-80. 

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